Over the past twenty years, studies have revealed the function and importance of cardiac transcription factors during heart development and in congenital heart disease. Interestingly, in the developing heart, Tbx5 and Tbx20 are expressed complementary in the left and right ventricles, respectively (Fig. 42.2) [6]. Moreover, Tbx5 is a key gene involved in the acquisition of the ventricular septum during vertebrate evolution [14].
Knockout mice for each gene show hypoplasia in the same region in which the gene is normally expressed (adapted from Bruneau et al. [8] and Takeuchi et al. [9]). Interestingly, turtles show a left-high versus right-low gradient of Tbx5 expression at late developmental stages and a septum-like structure forms in the middle of the ventricle (Fig. 42.3). These results strongly suggest that Tbx5 expression in the left ventricle is important for biventricular development.
In cardiac development, SWI/SNF-type chromatin remodeling factors play key roles in the differentiation of cardiomyocytes by interacting with cardiac-specific transcription factors [15,16]. When associated with Tbx5, Brg1, a core protein of the SWI/SNF-type chromatin remodeling complex, synergistically regulates cardiac differentiation in the presence of Baf60c [ 20 ]. Mice heterozygous for both Brg1 and Tbx5 had more severe defects than single mutants, particularly in the left ventricle (Fig. 42.6).
In the future, we must determine the role of epigenetic factors in heart failure because these factors regulate the transcription of cardiac genes (Fig. 42.7).
Introduction
PcG Functions in Cardiac Development
To address the role of PRC2 in cardiac development, Ezh2 and Eed were conditionally inactivated in specific cardiac cells using Nkx2-5:Cre or TnT:Cre [3,4]. Inactivation of Ezh2 by Nkx2-5:Cre (Ezh2NK) and Eed by TnT:Cre (EedTnT) resulted in embryonic lethality and various cardiac defects, including compact myocardial hypoplasia, while inactivation of Ezh2 by TnT:Cre (Ezh2TnT) did not result in major cardiac defects . defects in cardiogenesis despite modest upregulation of some cardiac genes, probably due to the redundant functions of Ezh1 and Ezh2. Embryos deficient in Ring1b, a core component of PRC1, also showed early embryonic lethality caused by gastrulation arrest [15].
Although early developmental arrest in Ring1bKO embryos was partially restored by inactivation of Cdkn2a. Canonical PRC1 binds to the H3K27me3 mark and mediates the mono-. ubiquitination of histone H2A at lysine 119. 43 Pcgf5 Contributes to PRC1 (Polycomb Repressive Complex 1) in Development. Ink4a/ARF), heart tissue did not develop in double-KO embryos.
In contrast to the early developmental defects seen in KO mice lacking some of the core PRC1 and PRC2 components, the absence of other components has been shown to cause limited effects. For example, loss of Rae28/Phc1 resulted in perinatal lethality with cardiac abnormalities, double-outlet right ventricles, and tetralogy of Fallot [ 6 , 7 ]. In addition to cardiac defects, Rae28/Phc1-deficient mice also exhibited craniofacial developmental defects, as well as thymus and parathyroid gland defects as seen in human DiGeorge syndrome.
Furthermore, Cbx4 mutant mice exhibited postnatal lethality with severe hypoplasia of the developing thymus as a result of reduced thymocyte proliferation. Thus, PcG proteins are essential for molecular regulation of the expression of several cardiac genes during embryogenesis and important for cardiac morphogenesis.
Diversity of PcG Proteins
Pcgf5 Expression in the Developing Heart
Conclusions
Ring1b Rae28/Phc1 E9.5
AVCRA
- Introduction
- miRNAs in Cardiac Development
- Cardiac Regeneration, Remodeling, and Ischemia Regulated by miRNAs
- LncRNAs in Cardiac Development
- Noncoding RNAs in Cardiac Disease
Images or other third-party material in this chapter are included in the work's Creative Commons license, unless otherwise indicated in the credit line; if such material is not included in the Creative Commons license of the work and the corresponding action is not permitted by legal regulations, users will need to obtain permission from the license holder to copy, adapt or reproduce the material. Targeted disruption of the mouse homologue of the drosophila polyhomeotic gene leads to altered anteroposterior patterning and neural crest defects. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene.
Roles for miRNAs have been demonstrated in the regulation of a wide range of biological activities and diseases [1]. Global disruption of all miRNA expression in the heart is the first step in understanding the function of miRNAs in cardiac development and physiology. Disruption of miRNA expression at the early embryonic stage using Nkx2.5-Cre results in improperly compacted ventricular myocardium in mutant embryos [4], and α-MHC-Cre-mediated conditional deletion of Dicer causes postnatal lethality due to dilated cardiomyopathy and heart failure [5].
More specifically, we identified miR-19a/b as the major contributors among the miR-17-92 cluster to the regulation of cardiomyocyte proliferation [8]. Cardiac remodeling, defined as a change in the structure of the heart (dimensions, mass, shape) is one of the most important responses of the heart to biomechanical stress and pathological stimuli. Several miRNAs participate in the regulation of these pathological processes, especially cardiomyocyte apoptosis after MI and I/R injury.
Equally critically, it will be important to determine whether the genetic mutation of the Braveheart gene is associated with human cardiovascular disorders. Fendrr, another novel lncRNA, has been identified as an essential regulator of heart and body wall development. development [16]. Although it is not yet fully understood how ANRIL works, evidence suggests that this lncRNA may participate in the regulation of histone methylation [ 18 ].
We have just entered the era of "non-coding". We look forward to seeing more and more reports on the roles of non-coding RNAs in the regulation of a variety of essential biological processes. MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction. MicroRNA-320 is involved in the regulation of cardiac ischemia/reperfusion injury by targeting heat shock protein 20.
The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Susceptibility to coronary artery disease and diabetes is encoded by several closely linked SNPs in the ANRIL locus on chromosome 9p.
- Introduction
- Modeling Fetal Cardiac Reprogramming in Hypoplastic Left Heart Syndrome (HLHS)
- hiPSCs to Model Williams-Beuren Syndrome (WBS)
- Future Directions and Clinical Applications
- Introduction
- A Broad View of Bioengineering Cardiac Tissues
- Immature Cells for Engineered Cardiac Tissues
In addition to the use of iPS cells for disease modeling and drug discovery, there are strong efforts to use pluripotent stem cells for regenerative medicine. Human pluripotent stem cells, which include human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), provide a unique in vitro platform for studying human "disease in a dish". In this chapter, we will discuss the use of human pluripotent stem cells to model human heart disease.
Human embryonic stem cells • Induced pluripotent stem cells • Williams syndrome • Hypoplastic left heart syndrome • Fetal reprogramming. Human embryonic stem cells (hESC) can give rise to all three germ layers—ectoderm, endoderm, and mesoderm—and can be used to generate differentiated cells of different lineages [1]. The Nobel Prize-winning discovery by Yamanaka of the ability to reprogram somatic cells into induced pluripotent stem cells (iPSC) using
HLHS is one of the most severe cardiac malformations, characterized by poor growth of left-sided cardiac structures. VEGF; regulation of TGFβ1; DNA damage (highest in endothelial cells, followed by myocytes, followed by SMCs); cell aging; decreased cell proliferation, resulting in a decrease in myocyte and endothelial lineages but an increase in SMC lineages; and decreased contractility (Figure 45.1). Cardiac manifestations are common and are mainly associated with haploinsufficiency of the elastin gene in the deleted region.
Treatment with rapamycin, an mTOR inhibitor and antiproliferative agent, showed partial rescue of the abnormal phenotype in WBS-SMCs by increasing differentiation, reducing proliferation, and improving tube-forming capacity. The ability to differentiate pluripotent stem cells into many different organ or cell types may allow the study of not only cardiac but also extracardiac phenotypes, especially in syndromic disorders, as recently shown in a patient with Timothy syndrome [17,18] . In summary, stem cell-derived pluripotent models are revolutionizing our understanding of disease pathogenesis and are positioned to accelerate drug screening and discovery especially for rare cardiac disorders with a genetic basis for which there are no available therapies and where clinical studies are challenging.
While the use of these cells for in vivo therapies is still several years away, this platform is well-positioned to study the molecular underpinnings of genetic heart disorders and help identify new therapies for tailored care of the affected child. Induction of pluripotent stem cells from cultures of mouse embryos and adult fibroblasts by defined factors. Modeling and rescuing the vascular phenotype of Williams-Beuren syndrome in patient-induced pluripotent stem cells.
Progressive maturation in contracting cardiomyocytes derived from human embryonic stem cells: Qualitative effects on electrophysiological responses to drugs. Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cells.
